+

WO2001053260A1 - Carboxamides utilises comme inhibiteurs de proteine de transfert triglyceridique microsomique et de la secretion d'apolipoproteine b - Google Patents

Carboxamides utilises comme inhibiteurs de proteine de transfert triglyceridique microsomique et de la secretion d'apolipoproteine b Download PDF

Info

Publication number
WO2001053260A1
WO2001053260A1 PCT/EP2001/000439 EP0100439W WO0153260A1 WO 2001053260 A1 WO2001053260 A1 WO 2001053260A1 EP 0100439 W EP0100439 W EP 0100439W WO 0153260 A1 WO0153260 A1 WO 0153260A1
Authority
WO
WIPO (PCT)
Prior art keywords
aryl
heteroaryl
lower alkyl
formula
trifluoromethyl
Prior art date
Application number
PCT/EP2001/000439
Other languages
English (en)
Inventor
Gary Michael Ksander
Original Assignee
Novartis Ag
Novartis-Erfindungen Verwaltungsgesellschaft Mbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novartis Ag, Novartis-Erfindungen Verwaltungsgesellschaft Mbh filed Critical Novartis Ag
Priority to AT01909632T priority Critical patent/ATE295836T1/de
Priority to EP01909632A priority patent/EP1259484B1/fr
Priority to AU2001237309A priority patent/AU2001237309A1/en
Priority to DE60110896T priority patent/DE60110896T2/de
Priority to US10/181,006 priority patent/US6878707B2/en
Priority to JP2001553264A priority patent/JP3897594B2/ja
Publication of WO2001053260A1 publication Critical patent/WO2001053260A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/12—One of the condensed rings being a six-membered aromatic ring the other ring being at least seven-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the invention relates to the compounds of formula I
  • R 2 -C, R 3 -C, R 4 -C or R5-C may be replaced by N; and wherein n is 1 , 2 or 3;
  • R] is aryl, heteroaryl or (aryl or heteroaryl)-lower alkoxy
  • R 2 , R 3 , Rt and R 5 are independently hydrogen, lower alkyl, lower alkoxy, halo, trifluoromethyl or cyano;
  • n 1, 2 or 3;
  • R 7 is hydrogen, lower alkyl, (aryl or heteroaryl)-lower alkyl, lower alkoxy, (aryl or heteroaryl)-lower alkoxy 1 , hydroxy, oxo, lower aJkylenedioxy or lower alkanoyloxy; W is O, S or NR 8 ;
  • R 8 is -COR a , -CON , -COOR d , -SO 2 R e , hydrogen, optionally substituted
  • R a , R ⁇ j and R e are independently optionally substituted lower alkyl, cycloalkyl, adamantyl, aryl, heteroaryl or (aryl or heteroaryl)-lower alkyl;
  • R and Rc are independently hydrogen, cycloalkyl, optionally substituted lower alkyl, aryl, heteroaryl or (aryl or heteroaryl) lower alkyl; or Rb and Rc together represent lower alkylene; and pharmaceutically acceptable salts thereof; and enantiomers thereof.
  • MTP microsomal triglyceride transfer protein
  • apoB apolipoprotein B
  • a particular embodiment of the invention relates to the compounds of formula I'
  • R 2 -C, R3-C, R4-C or R 5 -C may be replaced by N; and wherein n, and R ⁇ -R ⁇ have meaning as defined above; pharmaceutically acceptable salts thereof; and enantiomers thereof.
  • X is R 2 -C or N; and n, and Ri-Re have meaning as defined above; pharmaceutically acceptable salts thereof; and enantiomers thereof.
  • a particular aspect of the invention relates to the indane derivatives of formula lb
  • Ri is monocyclic aryl or heteroaryl
  • X is R 2 -C or N
  • R 2 , R 3 , R 4 and R5 are independently hydrogen, lower alkyl, halo, trifluoromethyl, cyano, or lower alkoxy; and Re has meaning as defined above; and pharmaceutically acceptable salts thereof; and enantiomer thereof.
  • R x is phenyl or phenyl substituted by fluoro, chloro, trifluoromethyl, cyano or lower alkyl
  • X is N or R 2 -C
  • R 2 , R 3 , R ⁇ and R 5 are independently hydrogen, lower alkyl, halo or trifluoromethyl
  • Re has meaning as defined above; and pharmaceutically acceptable salts thereof; and enantiomers thereof.
  • Particular aspects of the invention relate to the compounds of the formulae I, I', la, lb or lb' wherein Re is group of formula (i) wherein R 7 is (aryl or heteroaryl)-lower alkyl, lower alkoxy, (aryl or heteroaryl)-lower alkoxy, hydroxy, lower alkanoyloxy, oxo or lower alkylenedioxy, and m is 2; or R$ is group of formula (ii) wherein
  • W is NR 8 . and R 8 is -COR a , -CON , -COOR d , or -SO 2 R e ; and R a -R e have meaning as defined
  • R 2 is hydrogen, Cr -alkyl, CrC 4 -alkoxy, trifluoromethyl, chloro or fluoro;
  • R 8 is -COR a , -CON , -COOR d or -SO ⁇ ; R a -R e have meaning as defined abo
  • R 9 is trifluoromethyl, chloro or cyano; pharmaceutically acceptable salts thereof; and enantiomers thereof.
  • R 2 is hydrogen, methyl or trifluoromethyl; Rg is as defined above; R 9 is trifluoromethyl or chloro; pharmaceutically acceptable salts thereof; and enantiomers thereof.
  • R 2 is methyl; R 8 is -COORd wherein Rd is lower alkyl; and R 9 is trifluoromethyl; pharmaceutically acceptable salts thereof; and enantiomers thereof.
  • alkyl refers to straight or branched chain hydrocarbon groups having 1 to 20 carbon atoms, preferably lower alkyl of 1 to 7 carbon atoms.
  • exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl and the like.
  • optionally substituted alkyl refers to alkyl groups optionally substituted by e.g. one or more of the following groups: halo, CF 3 , hydroxy, alkoxy, alkoxyalkoxy, aryloxy, cycloalkyl, alkanoyl, alkanoyloxy, arnino, substituted amino, alkanoylamino, thiol, alkylthio, and the like.
  • alkylene referes to a straight chain bridge of 1 to 6 carbon atoms connected by single bonds (e.g., -(CH 2 ) X - wherein x is 1 to 6) which may be substituted with 1 to 3 lower alkyl groups.
  • lower alkyl refers to those alkyl groups as described above having 1 to 7, preferably 1 to 4 carbon atoms.
  • cycloalkyl refers to cyclic hydrocarbon groups of 3 to 8 carbon atoms, such as cyclopentyl, cyclohexyl or cycloheptyl.
  • adamantyl refers to 1- or 2-adamantyl, preferably 1 -adamantyl.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • alkoxy or "alkyloxy” refers to alkyl-O-.
  • aryl refers to carbocyclic monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, tetrahydronaphthyl, and biphenyl groups, each of which may optionally be substituted by one to four substituents such as alkyl, halo, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, substituted amino, alkanoylamino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, alkylsulfonyl, aminosulfonyl, and the like.
  • aralkyl refers to an aryl group linked to an alkyl group, such as benzyl.
  • heteroaryl refers to an aromatic heterocycle, for example monocyclic or bicyclic heterocyclic aryl, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuryl, and the like, optionally substituted by e.g., lower alkyl, lower alkoxy or halo, the point of attachment of said heterocycle being at a carbon atom of the heterocyclic ring.
  • Pharmaceutically acceptable salts of the compounds of the invention are particularly acid addition salts, such as of mineral acids, organic carboxylic, and organic sulfonic acids e.g., hydrochloric acid, methanesulfonic acid, maleic acid, and the like provided a basic group, such as pyridyl, constitutes part of the structure.
  • acid addition salts such as of mineral acids, organic carboxylic, and organic sulfonic acids e.g., hydrochloric acid, methanesulfonic acid, maleic acid, and the like provided a basic group, such as pyridyl, constitutes part of the structure.
  • the compounds of the invention depending on the nature of the substituents, possess one or more asymmetric carbon atoms, and therefore exist as racemates and the (R) and (S) enantiomers thereof. All are within the scope of the invention. Preferred is the more active enantiomer typically assigned the R-configuration (at the carbon bearing the R ⁇ substituent). Illustrative thereof are the compounds of formula lb (the R-isomers of the compound of formula lb).
  • Ri is monocyclic aryl or heteroaryl
  • X is R 2 -C or N
  • R 2 , R 3 , R and R5 are independently hydrogen, lower alkyl, halo, trifluoromethyl, cyano, or lower alkoxy
  • R ⁇ has meaning as defined above; and pharmaceutically acceptable salts thereof.
  • R 8 is a group that serves as an N-protecting group, e.g. -COOR d or SO 2 R e
  • Z is a leaving group such as halo (e.g. chloro) or alkylsulfonyloxy (e.g. methylsulfonyloxy), in the presence of abase; and, if appropriate, converting a compound so obtained to another compound of the invention; or
  • R 8 has meaning as defined above, under conditions of reductive amination; and, if appropriate, converting a compound so obtained into another compound of the invention.
  • process (b) can be carried out according to methodology well known in the art for the transformation involved, and illustrated in the example.
  • reductive amination of process (b) is carried out in the presence of e.g. sodium borohydride, sodium triacetoxyborohydride or polymer supported borohydride.
  • the condensation according to process (a) can be carried out in the presence of a tertiary amine, such as diisopropylethylamine, N-methylmorpholine, triethylamine or pyridine, optionally in the presence of an inert solvent such as methylene chloride.
  • a tertiary amine such as diisopropylethylamine, N-methylmorpholine, triethylamine or pyridine
  • an inert solvent such as methylene chloride.
  • a resulting compound wherein R 8 is arylsulfonyl, e.g. tosyl or lower alkoxycarbonyl (e.g. methoxycarbonyl) can be deprotected to a compound wherein Rs is hydrogen by treatment with, e.g. HBr in acetic acid, optionally in the presence of phenol.
  • Compounds wherein Rg is hydrogen can in turn be converted to other compounds of the invention by treatment with the appropriate alkylating or acylating agent, for example an appropriately substituted sulfonyl chloride, carboxylic acid chloride or anhydride, carbonic acid chloride, carbamoyl chloride or isocyanate.
  • the amine starting material for process (a) can be prepared by coupling a protected compound of e.g. formula II
  • R f is lower alkyl, with a reactive functional carboxylic acid derivative, e.g, a compound of formula HI
  • R 1 -R 5 and X have meaning as defined above, in the presence of a base such as N-methylmorpholine, dnsopropylethylarnine, triethylamine or pyridine to provide compounds of the formula IV
  • biarylcarboxylic acids corresponding to the compounds of formula HI can be prepared e.g. as described in Bioorg. Med. Chem. Lett. 7 (13), 1595 (1997).
  • amines of formula II are acylated with compounds of formula IX in the presence of a base such as N- methylmorpholine, d ⁇ sopropylethylamine or pyridine to give compounds of the formula X.
  • a base such as N- methylmorpholine, d ⁇ sopropylethylamine or pyridine
  • Palladium catalyzed aryl-aryl coupling of aryl boronic acids of formula (R ⁇ -B(OH) 2 ) with aryl bromides of the formula X (or iodides or triflates) gives compounds of formula IN.
  • Treatment with e.g. formic acid or trimethylsilyl iodide readily deprotects the nitrogen to give compounds of formula N.
  • ketone starting materials for process (b) can be prepared as illustrated in the scheme below, starting from 2-hydroxyindane.
  • Chiral compounds of the invention can be prepared from chiral intermediates as follows:
  • chiral compounds of the invention can be prepared e.g., by acylating a protected arriine of e.g. formula XI
  • a compound of the formula XV is then coupled with a compound of formula El in the presence of a base such as N-methylmorpholine, diisopropylethylamine, triethylamine, or pyridine to provide e.g. a compound of formula XVI
  • Amines of formula V are then reacted as previously described to obtain the enantiomers corresponding to the compounds of formula lb.
  • a method for the preparation of enantiomers of the compounds of the invention thus comprises:
  • (R)-2-Arnino-5-bromoindane can be prepared e.g. by treating racemic 2-amino-5- bromoindane with 1(S)- 10-camphorsulfonic acid, selectively crystallizing and purifying the resulting (R,S) diastereomeric salt, and then liberating, by treatment with a base, (R)-2-amino- 5-bromoindane which is substantially free of the (S)-isomer.
  • racemic 2-amino-5-bromoindane is prepared by bromination of 2-arninoindane which is commercially available or is prepared by converting ninhydrin to l,3-dioxo-2- hydroxyiminoindane followed by catalytic hydrogenation.
  • the Buchwald amination by condensation of e.g. 5-bromo-2-carbomethoxyaminoindane with benzophenone imine can be carried out similarly to the procedures described in Tetrahedron Letters 38, 6367 (1997).
  • the amination is carried out in the presence of a palladium catalyst, a ligand and a base in an inert solvent such as toluene.
  • Palladium catalysts include tris(dibenzylideneacetone)dipalladium (O), bis(dibenzylideneacetone) ⁇ alladium (O) and palladium acetate.
  • Preferred ligands include 2,2-bis(diphenylphosphino-l,l -binaphthyl, bis(2- diphenylphosphinophenyl)ether and 1,1 -bis(diphenylphosphino)ferrocene.
  • Preferred bases include sodium methoxide and sodium isopropoxide. The resulting benzophenone imines are cleaved to the free amines, e.g. by treatment with dilute acid, such as 2N hydrochloric acid.
  • protecting groups are to protect the functional groups from undesired reactions with reaction components under the conditions used for carrying out a desired chemical transformation.
  • the need and choice of protecting groups for a particular reaction is known to those skilled in the art and depends on the nature of the functional group to be protected (hydroxy group, amino group, etc.), the structure and stability of the molecule of which the substituent is a part and the reaction conditions.
  • reactive functional derivatives of carboxylic acids represent, for example, anhydrides (especially mixed anhydrides), acid halides, acid azides, lower alkyl esters, and activated esters thereof.
  • Mixed anhydrides are preferably such from pivalic acid, or a lower alkyl (ethyl, isobutyl) hemiester of carbonic acid; acid halides are for example chlorides or bromides; activated esters for example succinimido, phthalimido or 4- nitrophenyl esters; lower alkyl esters are for example the methyl or ethyl esters.
  • the new compounds may be in the form of one of the possible isomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, optical isomers (antipodes), racemates, or mixtures thereof.
  • the aforesaid possible isomers or mixtures thereof are within the purview of this invention.
  • Any resulting mixtures of isomers can be separated on the basis of the physico-chemical differences of the constituents, into the pure geometric or optical isomers, diastereoisomers, racemates, for example by cbiOmatography and/or fractional crystallization, or resolved by enzymatic resolution.
  • any resulting racemates of intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereoisomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • the amine intermediates can thus be resolved into their optical antipodes e.g., by fractional crystallization of salts of d- or 1-carboxylic acids (e.g., d-or 1-tartaric acid or d- or 1- camphorsulfonic acid).
  • Racemic products can also be resolved by chiral chromatography, e.g., high-pressure liquid chromatography using a chiral absorbent.
  • Compounds of the invention having basic groups can be converted into acid addition salts, especially pharmaceutically acceptable salts.
  • inorganic acids such as mineral acids, for example sulfuric acid, a phosphoric or hydrohalic acid
  • organic carboxylic acids such as (CrC 4 )-alkanecarboxylic acids which, for example, are unsubstituted or substituted by halogen
  • acetic acid such as saturated or unsaturated dicarboxylic acids, for example oxalic, succinic, maleic or fumaric acid, such as hydroxycarboxylic acids, for example glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid
  • organic sulfonic acids such as (C C 4 )-alkylsulfonic acids (for example methanesulfonic acid) or arylsulfonic acids which are unsubstituted or substituted (for example by
  • the compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • compositions according to the invention are those suitable for enteral, such as oral or rectal, transdermal and parenteral administration to mammals, including man, to inhibit microsomal triglyceride transfer protein (MTP) and apolipoprotein B (apo B) secretion, and for the treatment of disorders responsive thereto, comprising an effective amount of a pharmacologically active compound of the invention, alone or in combination, with one or more pharmaceutically acceptable carriers.
  • enteral such as oral or rectal, transdermal and parenteral administration to mammals, including man, to inhibit microsomal triglyceride transfer protein (MTP) and apolipoprotein B (apo B) secretion, and for the treatment of disorders responsive thereto, comprising an effective amount of a pharmacologically active compound of the invention, alone or in combination, with one or more pharmaceutically acceptable carriers.
  • MTP microsomal triglyceride transfer protein
  • apo B apolipoprotein B secretion
  • the pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipients or carriers suitable for either enteral or parenteral application.
  • Preferred are tablets and gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or efferv
  • compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
  • Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to75%, preferably about 1 to 50%, of the active ingredient.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • Suitable formulations for topical application are preferably aqueous solutions, ointments, creams or gels well known in the art.
  • the pharmaceutical formulations contain an inhibiting amount of a compound of the invention as defined above, either alone or in combination with another therapeutic agent, e.g., each at an effective therapeutic dose as reported in the art.
  • therapeutic agents are well known in the art.
  • a compound of the invention may be administered either simultaneously, before or after the other active ingredient, either separately by the same or different route of administration or together in the same pharmaceutical formulation.
  • the dosage of active compound administered is dependent on the species of warmblooded animal (mammal), the body weight, age and individual condition, and on the form of adrninistration.
  • a unit dosage for oral administration to a mammal of about 50 to 70 kg may contain between about 1 and 1000 mg, advantageously between about 10 and 500 mg of the active ingredient, preferably between about 10 and 100 mg.
  • the present invention also relates to methods of using the compounds of the invention and their pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in mammals for the treatment of elevated levels of MTP and of apo B and conditions related thereto.
  • the compounds of the invention are inhibitors of microsomal triglyceride transfer protein (MTP) and of apolipoprotein B (apo B) secretion and are thus useful for lowering serum lipid levels, including serum triglyceride and serum cholesterol levels.
  • MTP microsomal triglyceride transfer protein
  • apo B apolipoprotein B
  • Such compounds are therefore useful for the treatment and prevention of hyperlipedemia, hypercholesterolemia and hypertriglyceridemia and diseases associated therewith, e.g., cardiovascular diseases including cardiac ischemia, atherosclerosis and its clinical sequelae, as well as obesity, pancreatitis and diabetes.
  • the compound of Example 14 demonstrates an IC50 of about 2nM in the apo B assay and an IC5 0 of about 40 nM in the MTP assay.
  • the compound of example 14 lowers both plasma triglycerides and cholesterol at a dose of 5 mg/kg. p.o. Accordingly, the present invention relates to a method of inhibiting microsomal triglyceride transfer protein; decreasing apolipoprotein B secretion and treating microsomal triglyceride transfer protein or apolipoprotein B dependent conditions in mammals which comprises administering to a mammal in need thereof an effective amount of a compound of the present invention.
  • the present invention relates to the use of a compound according to the present invention for the manufacture of a medicament for inhibiting microsomal triglyceride transfer protein; decreasing apolipoprotein B secretion and treating microsomal triglyceride transfer protein or apolipoprotein B dependent conditions and related conditions and diseases.
  • methyl 6-methyl-4'-trifluoromethyl-l,r-biphenyl-2-carboxylate can be prepared as follows:
  • 6-methyl-4'-trifluoromethyl-l,r-biphenyl-2-carboxylic acid can be prepared as follows:
  • 3-Methylsalicylic acid is esterified to methyl 3-methylsalicylate by reaction under reflux for about 48 hours with methanol in the presence of trimethyl orthoformate (4.0 moles) and concentrated sulfuric acid (1.1 moles) while removing by distillation the generated methyl formate and replacing the methanol which is lost by distillation.
  • the reaction mixture is then evaporated to dryness at 40° under vacuum and toluene is added.
  • the toluene solution is washed with water, then 20% aqueous potassium bicarbonate solution and saturated sodium chloride solution.
  • the toluene solution is filtered through neutral activated aluminum oxide and evaporated to dryness to yield methyl 3-methylsalicylate as a liquid.
  • a solution of 155 g of methyl 3-methyl-2-trifluoromethylmethanesulfonyloxybenzoate, 107.8 g of potassium carbonate in 467.5 mL of THF and 935 g of deionized water is stirred under nitrogen for 20 minutes.
  • 15.0 g of Tetrakis(triphenylphosphine)palladium (0) and -1610 mL of boronate solution from step above are added and the reaction mixture is heated under gentle reflux ( ⁇ 64°C) for 16 hours.
  • the reaction mixture is cooled to room temperature and filtered through a pad of 40 g of the filter agent Celite ® 521.
  • the filter cake is washed with 100 mL of THF and the total filtrate is partially evaporated under reduced pressure (110-120 mbar/40°C) to remove about 1500 mL of distillate and obtain a three phase mixture (about 1250 mL).
  • 500 mL of t-Butyl methyl ether and 200 mL of 2% sodium chloride solution are added.
  • the mixture is stirred for 5 minutes and filtered through a pad of 40 g of Filter agent, Celite ® 521 and the filter cake is washed with 100 mL of f-butyl methyl ether.
  • the top organic layer (1100 mL) is separated from the bottom aqueous layer (950 mL).
  • the bottom aqueous layer (950 mL) is extracted with 300 mL of t-butyl methyl ether.
  • the combined upper organic phases are washed with 300 mL of 2% sodium chloride solution and evaporated under reduced pressure (28 mbar/40°C) to obtain methyl 6-methyl-4'-trifluoromethyl-biphenyl-2-carboxylate.
  • the organic layer is separated and the aqueous layer is washed with 250 mL of heptane.
  • the aqueous layer is acidified with 500 mL of 4N hydrochloric acid and extracted with ethyl acetate.
  • the ethyl acetate extract is washed with water and filtered through the filter agent Celite ® 521.
  • the ethyl acetate solution (ca.1000 mL) is evaporated under reduced pressure (110-120 mbar/40°C) to a volume of 600 mL to which is added heptane (3125 mL).
  • the suspension is then heated to reflux until a clear solution is obtained, the solution is cooled to 0°C and the resulting solid is filtered off to yield 6-methyl-4'-trifluoromethyl-l,r-biphenyl-2- carboxylic acid.
  • ninhydrin 33 g, 0.185 mol
  • acetic acid 554 g
  • Sulfuric acid is then added (54.42 g, 0.555 mol) followed by hydroxylamine sulfate (31.63 g, 0.193 mol).
  • the mixture is heated to 55°C for 30 minutes and is then allowed to cool to room temperature.
  • 10% Pd/C (2.64 g, 8% w/w) is added to the resulting yellow suspension and the mixture is hydrogenated at a pressure of H 2 of 20 psi.
  • the H 2 pressure is increased to 40 psi and the temperature increased to 35°C.
  • the reaction is allowed to cool before filtration on a pad of Celite (20 g).
  • the Celite cake is washed with acetic acid (70 g).
  • the filtrate is concentrated, xylene (250 g) is added to the resulting slurry and the mixture concentrated again.
  • Xylene (170 g) is added followed by slow addition of 20% NaOH (367 g) until a basic pH and a clear separation of the organic and aqueous layers is obtained.
  • the xylene layer is then separated and filtered.
  • the HC1 salt is then precipitated out by slow addition of a 4 N HC1 solution in 1-pentanol (51 g).
  • the suspension is cooled to 0°C and filtered.
  • the cake is rinsed with heptane (100 g) and dried under vacuum to yield 2- aminoindane hydrochloride as a white powder.
  • a solution of 118.8 g of 2-aminoindane hydrochloride in 594 mL of water is heated to a temperature of 58-60°C and 120.0 g of bromine is added over a period of 50 minutes while maintaining an internal temperature at 58 to 62°C.
  • the mixture is stirred at 60-62°C for 1 hour and 107 mL of hydrobromic (48%) is added over a period of 5 minutes while maintaining the internal temperature of 60-62°C.
  • the mixture is stirred for an additional 10 minutes.
  • the reaction mixture is cooled to an internal temperature of 20-23°C over a period of 1 hour.
  • the resulting solid is collected by filtration and washed with 3 x 20 mL of water (precooled to 0-5°C), and dried at 60-65°C under vacuum (10-30 torr) with nitrogen bleeding to obtain ( ⁇ )-5-bromo-2-aminoindane hydrobromide.
  • a mixture of 130.0 g of ( ⁇ )-5-bromo-2-aminoindane hydrobromide and 1500 mL of isopropyl acetate is stirred at 20-25°C under nitrogen.
  • a solution (precooled to 20-25°C) of 26.62 g of sodium hydroxide and 186.35 g of sodium chloride in 750 mL of water is added over a period of 5 minutes while maintaining an internal temperature at 20-25°C.
  • the suspension is stirred efficiently until all the solid dissolves (30 minutes).
  • the organic layer is separated and the aqueous layer is extracted with 750 mL of isopropyl acetate.
  • the organic layers are combined to afford -2330 mL of a solution of ( ⁇ )-5-bromo-2-aminoindane free base.
  • To the above solution is added 1300 mL of isopropyl acetate and 930 mL of methanol.
  • the solution is stirred under nitrogen and heated to an internal temperature of 65 °C to achieve a gentle refluxing, over a period of 15 minutes.
  • a solution of 60 g of sodium bicarbonate in 600 mL of water is added and the resulting white slurry is stirred under nitrogen and cooled to a temperature of 0-5°C over a period of 15 minutes.
  • a solution of 35.4 g of methyl chloroformate in 200 mL of isopropyl acetate is added over a period of 45 minutes while maintaining an internal temperature of 0-5°C and the mixture is stirred at this temperature for an additional 1 hour.
  • the organic layer is separated and washed with 150 mL of 1 N sulfuric acid is added, then with a solution of 10 g of sodium bicarbonate in 100 mL of deionized water and finally with 150 mL of deionized water.
  • the organic layer is concentrated under vacuum (100-300 torr) at a temperature of 40-50°C to -150 mL of a slurry.
  • Heptane (500 mL) is added and the mixture is again concentrated under vacuum (100-200 torr) at a temperature of 40-50°C to about 300 mL of a slurry.
  • Heptane (500 mL) is again added and the mixture is cooled to an internal temperature of 0-5°C.
  • the solid is collected and washed with 40 mL of heptane in two equal portions of 20 mL each.
  • the solid is dried at 60-65 °C under vacuum (10-30 torr) to obtain (R)-(5-bromoindan 2-yl)-carbamic acid methyl ester as a crystalline white solid.
  • the solid is collected by filtration and washed with 438 mL of water in two equal portions.
  • the solid is dried at 55-60°C under vacuum (10- 30 torr) with nitrogen bleeding to obtain crude (R)-(5-amino-indan-2-yl)-carbamic acid methyl ester as a solid.
  • a mixture of crude (R)-(5-amino-indan-2-yl)-carbamic acid methyl ester, activated carbon (about 0.15 times weight of the weight of crude material) and methanol (about 20 times volume of the weight of crude material) is stirred and heated to an internal temperature at 65 °C to achieve a gentle refluxing over a period of 15 minutes.
  • the mixture is stirred at this temperature for an additional 2 hours and filtered through celite to afford a solution of (R)-(5- aminoindan-2-yl)-carbamic acid methyl ester.
  • the solution is concentrated under vacuum (200-400 torr) at an internal temperature of 45-55°C to a small volume. Water is added (the ratio of methanol and water should be about 1:1).
  • 2-(4-Trifluoromethyl-phenyl)-nicotinic acid methyl ester is prepared by palladium [PdCl 2 (dppf)] catalyzed coupling of 2-chloronicotinic acid methyl ester (1.45 g, 8.45 mmol) and 4-trifluoromethylbenzeneboronic acid (2.41 g, 12.68 mmol) to give an oil: ] H NMR (CDC1 3 , 300 MHz): ⁇ 8.80 (IH, dd), 8.19 (IH, dd), 7.67 (4H, q), 7.40 (IH, dd), 3.70 (3H, s). MS (ES+) m z 282 (M+l).
  • Step A To 2-indanol (13.4g, 100 mmol) in 100 mL of methylene chloride at 0°C are added pyridine (8 mL), acetyl chloride (7.11 mL, 100 mmol) and dimethylaminopyridine (1.22 g, 10 mmol). After 1 hour an additional 4 mL of pyridine and 3.5 mL of acetyl chloride are added. The mixture is stirred for 1 hour and quenched with sodium bicarbonate. The organics are washed with IN HC1, brine, and dried over sodium sulfate. The mixture is filtered and concentrated to give 2-acetoxyindane as a solid.
  • Step B To a 0°C solution of 2-acetoxyindane from Step A (17.6 g, 100 mmol) in 35 mL of trifluoroacetic acid (TFA) is added fuming nitric acid (25.5mL, 625 mmol) dropwise. The solution is stirred for 4 hours, then concentrated in vacuo and poured into water. The mixture is extracted with methylene chloride and the extract is washed with sodium bicarbonate and brine, filtered and concentrated. The residue is slurred with ether. The product is collected and dried to give 2-acetoxy-5-nitroindane as a light yellow solid. Step C.
  • TFA trifluoroacetic acid
  • a solution of nitro compound from Step B (10 g, 45 mmol) in ethyl acetate (150 mL) is degassed and 10% palladium on carbon (1 g) added.
  • the reaction is evacuated and placed under 50psi of hydrogen gas for 4 hours. Filtration of the reaction mixture through celite is followed by concentration of the filtrate to give 5-amino-2- acetoxyindane.
  • Step D To a solution of the amine from Step C (1.44 g, 7.54 mmol) in methylene chloride (100 mL) and pyridine (0.73 mL, 9.05 mmol) at 0°C is added 6-methyl-4'- trifluoromethyl-l,r-biphenyl-2-carboxylic acid chloride (2.38 g, 8.0 mmol). The reaction mixture is stirred at room temperature overnight. The mixture is washed with IN HC1, sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated.
  • Step E To a solution of the amide from Step D (3.0 g, 6.62 mmol) in THF (50 mL) and methanol (20 mL) is added IN NaOH (13.24 mL, 13.24 mmol). The reaction is stirred for 90 minutes, then concentrated in vacuo. The residue is extracted with ethyl acetate and the organic layer is washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Crystallization from ether / hexanes gives the 6- methyl-4'-trifluoromethyl- 1 , 1 '-biphenyl-N-(2-hydroxyindan-5-yl)-2-carboxamide.
  • Step F To a solution of the alcohol from Step E (2.18 g, 5.3 mmol) in methylene chloride
  • Step G To a solution of the ketone from Step F (0.55 g, 1.35 mmol) in toluene (50 mL) is added p-toluenesulfonic acid (0.025g, 0.13 mmol) and N-carbomethoxypiperazine (0.213 g, 1.46 mmol). The mixture is refluxed overnight with the removal of water using a Dean-Stark condenser.
  • Step H To a solution of the compound from Step G (0.66 g, 1.23 mmol) in dichloroethane (10 mL) is added glacial acetic acid (0.71 mL, 1.23 mmol) followed by the addition of sodium triacetoxyborohydride (0.385 g, 1.73 mmol). The mixture is stirred overnight, poured into IN NaOH, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and concentrated to give the desired racemic compound; mp 161-163°C; MS (ES+), m z 538 (M+1).
  • the starting material N,N-bis-(2-chloroethyl)-carbamic acid methyl ester is prepared by treating a solution of bis-(2-chloroethyl)-amine hydrochloride in methylene chloride at 0°C with methyl chloroformate ( 1.0 mole equivalent) and du ⁇ opropylethylamine ( 2.2 mole equivalents).
  • the starting material, ⁇ T,-V-bis(2-chloroethyl)-p-toluenesulfonamide is prepared by treating a solution of bis-(2-chloroethyl)-amine hydrochloride is methylene chloride at 0°C with p-toluenesulfonyl chloride ( 1.0 mole equivalent) and dfeopropylethylamine ( 2.2 mole equivalents).
  • Example 32 Prepared similarly to Example 32 is 6-methyl-4 -trifluoromethyl- 1,1 -biphenyl-N-[2-[4- (4-pyridinyl)piperazino]-indan-5-yl]-2-carboxamide; mp 135-138°C; MS (ES+), m/z 557 (M+1).
  • the amine is treated with methyl chloroformate, nitrated, reduced and acylated with 6- methyl-4 -trifluoromethyl- 1 , 1 -biphenyl-2-carboxylic acid chloride.
  • the product is N- deprotected to the primary amine which is treated with N,N-bis(2-chloroethyl) carbamic acid methyl ester under conditions similar to those described above for indane derivatives to give the title compound.
  • the title compound is prepared similarly to previous examples using 2-(4- trifluoromethyl-phenyl)-nicotinic acid chloride as starting material.
  • Hard gelatin capsules comprising 50 mg active substance can be prepared, for example, as follows:
  • Composition for 1000 capsules
  • Microcrystalline cellulose 30.0 g Sodium Lauryl sulfate 2.0 g Magnesium stearate 8.0 g
  • the sodium lauryl sulfate is added to the active ingredient via a sieve with a mesh size of 0.2 mm. Both components are intimately mixed. Then first the lactose is added via a sieve with a mesh size of 0.6 mm and then the microcrystalline cellulose via a sieve with a mesh size of 0.9 mm. Thereupon these components are intimately mixed for a further 10 minutes. Finally the magnesium stearate is added via a sieve with a mesh size of 0.8 mm. After 3 minutes of further mixing, the formulation is filled into hard gelatin capsules of size 0 (340 mg each).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Obesity (AREA)
  • Diabetes (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Peptides Or Proteins (AREA)
  • Pyridine Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Composés de formule (I) dans laquelle R2-C, R3-C, R4-C ou R5-C peuvent être remplacés par N, et n est égal à 1, 2 ou 3; R1 désigne un aryle, un hétéroaryle ou un (aryl ou hétéroaryl)-alcoxy inférieur; R2, R3, R4 et R5 désignent, indépendamment, un hydrogène, alkyle inférieur, alcoxy inférieur, halo, trifluorométhyle ou cyano; R6 désigne (i) ou (ii) ; m est égal à 1, 2 ou 3; R7 désigne un hydrogène, un alkyle inférieur, (aryl or hétéroaryl)-alkyle inférieur, un alcoxy inférieur, (aryl or hétéroaryl)-alcoxy inférieur, hydroxy, oxo, alkylènedioxy inférieur ou alcanoyloxy inférieur ; W désigne O, S ou NR8 où R8 désigne -CORa, (iii), -COORd, -SO2Re, un hydrogène, un alkyle inférieur, aryle, hétéroaryle ou (aryl or hétéroaryl)-alkyle inférieur éventuellement substitué; Ra, Rd et Re désignent, indépendamment, un alkyle inférieur, cycloalkyle, adamantyle, aryle, hétéroaryle ou un(aryl or hétéroaryl)-alkyle inférieur éventuellement substitué; Rb et Rc désignent, indépendamment, un hydrogène, cycloalkyle, un alkyle inférieur, aryle, hétéroaryle ou (aryl ou hétéroaryl) alkyle inférieur éventuellement substitué ; ou bien Rb et Rc représentent, conjointement, un alkylène inférieur. L'invention concerne en outre les sels pharmaceutiquement acceptables de ces composés, et des énantiomères de ceux-ci, qui sont utilisés comme inhibiteurs de protéine de transfert triglycéridique microsomique (MTP) et de la sécrétion d'apolipoprotéine B (apoB).
PCT/EP2001/000439 2000-01-18 2001-01-16 Carboxamides utilises comme inhibiteurs de proteine de transfert triglyceridique microsomique et de la secretion d'apolipoproteine b WO2001053260A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
AT01909632T ATE295836T1 (de) 2000-01-18 2001-01-16 Carboxamide und ihre verwendung als inhibitoren des mikrosomalen triglycerid-transfer-proteins und der apolipoprotein b (apo b) sekretion
EP01909632A EP1259484B1 (fr) 2000-01-18 2001-01-16 Carboxamides utilises comme inhibiteurs de proteine de transfert triglyceridique microsomique et de la secretion d'apolipoproteine b
AU2001237309A AU2001237309A1 (en) 2000-01-18 2001-01-16 Carboxamides useful as inhibitors of microsomal triglyceride transfer protein and of apolipoprotein b secretion
DE60110896T DE60110896T2 (de) 2000-01-18 2001-01-16 Carboxamide und ihre verwendung als inhibitoren des mikrosomalen triglycerid-transfer-proteins und der apolipoprotein b (apo b) sekretion
US10/181,006 US6878707B2 (en) 2000-01-18 2001-01-16 Carboxamides useful as inhibitors of microsomal triglyceride transfer protein and of apolipoprotein b secretion
JP2001553264A JP3897594B2 (ja) 2000-01-18 2001-01-16 ミクロソームトリグリセリド輸送タンパク質およびアポリポタンパク質分泌の阻害剤として有用なカルボキサミド

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US48397100A 2000-01-18 2000-01-18
US09/483,971 2000-01-18

Publications (1)

Publication Number Publication Date
WO2001053260A1 true WO2001053260A1 (fr) 2001-07-26

Family

ID=23922216

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2001/000439 WO2001053260A1 (fr) 2000-01-18 2001-01-16 Carboxamides utilises comme inhibiteurs de proteine de transfert triglyceridique microsomique et de la secretion d'apolipoproteine b

Country Status (9)

Country Link
US (1) US6878707B2 (fr)
EP (1) EP1259484B1 (fr)
JP (1) JP3897594B2 (fr)
AT (1) ATE295836T1 (fr)
AU (1) AU2001237309A1 (fr)
DE (1) DE60110896T2 (fr)
ES (1) ES2240420T3 (fr)
PT (1) PT1259484E (fr)
WO (1) WO2001053260A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001096327A1 (fr) * 2000-06-01 2001-12-20 Glaxo Group Limited Derives de benzamide bio-isosteriques et leur utilisation comme inhibiteurs de secretion d'apob-100
US6720351B2 (en) 2001-06-28 2004-04-13 Pfizer Inc. Triamide-substituted heterobicyclic compounds
WO2007120827A2 (fr) * 2006-04-14 2007-10-25 Novartis Ag Utilisation de biarylcarboxamides dans le traitement de troubles associés à la voie hedgehog
US7432392B2 (en) 2003-08-29 2008-10-07 Japan Tobacco Inc. Ester derivatives and medical use thereof
US7625948B2 (en) 2002-02-28 2009-12-01 Japan Tobacco Inc. Ester compound and medicinal use thereof
US8101774B2 (en) 2004-10-18 2012-01-24 Japan Tobacco Inc. Ester derivatives and medicinal use thereof

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9703379D0 (sv) * 1997-09-18 1997-09-18 Astra Ab New compounds
GB0121214D0 (en) * 2001-08-31 2001-10-24 Btg Int Ltd Synthetic method
WO2006113910A2 (fr) * 2005-04-19 2006-10-26 Surface Logix, Inc. Inhibiteurs des secretions microsomales des apo-b et des proteines de transfert des triglycerides
WO2006129193A2 (fr) * 2005-05-27 2006-12-07 Pfizer Products Inc. Polytherapie pour le traitement de l'obesite ou le maintien du poids apres une perte ponderale
US7803778B2 (en) 2006-05-23 2010-09-28 Theracos, Inc. Glucose transport inhibitors and methods of use
LT2187742T (lt) 2007-08-23 2018-01-10 Theracos Sub, Llc (2s,3r,4r,5s,6r)-2-(4-chlor-3-benzilfenil)-6-(hidroksimetil)tetrahidro-2h-piran-3,4,5-triolio dariniai, skirti panaudoti diabeto gydymui
TWI523652B (zh) * 2008-07-15 2016-03-01 泰瑞克公司 氘化苄基苯衍生物及使用方法
RU2624506C2 (ru) 2009-04-29 2017-07-04 АМАРИН КОРПОРЕЙШН ПиЭлСи Фармацевтические композиции, содержащие ера и сердечно-сосудистое средство, и способы их применения
WO2011153712A1 (fr) 2010-06-12 2011-12-15 Theracos, Inc. Forme cristalline d'inhibiteur de sglt2 de type benzyl-benzène
EP2600716A4 (fr) 2010-08-03 2014-02-19 Beth Israel Hospital Procédés et compositions pour le traitement de troubles métaboliques
TW201302681A (zh) 2011-03-25 2013-01-16 Abbott Lab Ｔｒｐｖ１拮抗劑
WO2013096223A1 (fr) 2011-12-19 2013-06-27 Abbvie Inc. Antagonistes de trpv1
WO2013096226A1 (fr) 2011-12-19 2013-06-27 Abbvie Inc. Antagonistes de trpv1
US8796328B2 (en) 2012-06-20 2014-08-05 Abbvie Inc. TRPV1 antagonists
CN110105333A (zh) * 2019-04-29 2019-08-09 武汉华星光电半导体显示技术有限公司 电致发光材料、电致发光材料的制备方法及发光器件

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998023593A1 (fr) * 1996-11-27 1998-06-04 Pfizer Inc. AMIDES INHIBANT LA SECRETION D'Apo B ET/OU LA PROTEINE MTP
WO2000005201A1 (fr) * 1998-07-21 2000-02-03 Novartis Ag Derives n-benzocycloalkyl-amide et leur utilisation comme medicaments
WO2000032582A1 (fr) * 1998-12-03 2000-06-08 Glaxo Group Limited Derives benzamidiques et leur utilisation comme inhibiteurs de la secretion d'apob-100
WO2001005767A1 (fr) * 1999-07-20 2001-01-25 Novartis Ag Composes organiques

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3832571A1 (de) * 1988-09-24 1990-05-31 Boehringer Ingelheim Kg Verwendung von 2,7-diamino-1,2,3,4-tetrahydronaphthalinen als arzneimittel, neue 2,7-diamino-1,2,3,4-tetrahydronaphthaline sowie verfahren zu ihrer herstellung
DE69422044T2 (de) 1993-08-06 2000-05-31 Pharmacia & Upjohn Co., Kalamazoo 2-aminoindane als selektive dopamin-d3-liganden
US5597826A (en) * 1994-09-14 1997-01-28 Pfizer Inc. Compositions containing sertraline and a 5-HT1D receptor agonist or antagonist
ZA96211B (en) 1995-01-12 1996-07-26 Teva Pharma Compositions containing and methods of using 1- aminoindan and derivatives thereof and process for preparing optically active 1-aminoindan derivatives
RU2161601C2 (ru) * 1995-02-01 2001-01-10 Фармация Энд Апджон Компани 2-аминоинданы в качестве селективных лигандов допамина д3
WO1996036596A1 (fr) 1995-05-19 1996-11-21 Chiroscience Limited 3,4-phenylsulfamides disubstitues et leur utilisation therapeutique
ATE233734T1 (de) * 1995-06-07 2003-03-15 Pfizer Biphenyl-2-carbonsäure-tetrahydro-isochinolin-6 yl amid derivate, deren hestellung und deren verwendung als inhibitoren des mikrosomalen triglycerid-transfer-proteins und/oder der apolipoprotein b (apo b) sekretion
US5675024A (en) * 1995-11-22 1997-10-07 Allergan Aryl or heteroaryl amides of tetrahydronaphthalene, chroman, thiochroman and 1,2,3,4,-tetrahydroquinoline carboxylic acids, having an electron withdrawing substituent in the aromatic or heteroaromatic moiety, having retinoid-like biological activity
US5965606A (en) 1995-12-29 1999-10-12 Allergan Sales, Inc. Methods of treatment with compounds having RAR.sub.α receptor specific or selective activity
DE69715188T2 (de) * 1996-04-30 2003-01-02 Pfizer Inc., New York Verfahren und zwischenprodukte zur herstellung von 4-trifluoromethylbiphenyl-2-carbonsaüre,(2-(2h-(1,2,4) triazol-3-ylmethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide
US6083986A (en) 1996-07-26 2000-07-04 Icagen, Inc. Potassium channel inhibitors
FR2769312B1 (fr) * 1997-10-03 1999-12-03 Adir Nouveaux composes de l'indanol, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
US6197798B1 (en) * 1998-07-21 2001-03-06 Novartis Ag Amino-benzocycloalkane derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998023593A1 (fr) * 1996-11-27 1998-06-04 Pfizer Inc. AMIDES INHIBANT LA SECRETION D'Apo B ET/OU LA PROTEINE MTP
WO2000005201A1 (fr) * 1998-07-21 2000-02-03 Novartis Ag Derives n-benzocycloalkyl-amide et leur utilisation comme medicaments
WO2000032582A1 (fr) * 1998-12-03 2000-06-08 Glaxo Group Limited Derives benzamidiques et leur utilisation comme inhibiteurs de la secretion d'apob-100
WO2001005767A1 (fr) * 1999-07-20 2001-01-25 Novartis Ag Composes organiques

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001096327A1 (fr) * 2000-06-01 2001-12-20 Glaxo Group Limited Derives de benzamide bio-isosteriques et leur utilisation comme inhibiteurs de secretion d'apob-100
US6720351B2 (en) 2001-06-28 2004-04-13 Pfizer Inc. Triamide-substituted heterobicyclic compounds
US6949572B2 (en) 2001-06-28 2005-09-27 Pfizer Inc. Triamide-substituted heterobicyclic compounds
US6979692B2 (en) 2001-06-28 2005-12-27 Pfizer Inc. Triamide-substituted heterobicyclic compounds
US7348355B2 (en) 2001-06-28 2008-03-25 Pfizer Inc. Triamide-substituted heterobicyclic compounds
US7482368B2 (en) 2001-06-28 2009-01-27 Pfizer Inc Triamide-substituted heterobicyclic compounds
US7625948B2 (en) 2002-02-28 2009-12-01 Japan Tobacco Inc. Ester compound and medicinal use thereof
US7432392B2 (en) 2003-08-29 2008-10-07 Japan Tobacco Inc. Ester derivatives and medical use thereof
US8101774B2 (en) 2004-10-18 2012-01-24 Japan Tobacco Inc. Ester derivatives and medicinal use thereof
WO2007120827A2 (fr) * 2006-04-14 2007-10-25 Novartis Ag Utilisation de biarylcarboxamides dans le traitement de troubles associés à la voie hedgehog
WO2007120827A3 (fr) * 2006-04-14 2007-12-13 Novartis Ag Utilisation de biarylcarboxamides dans le traitement de troubles associés à la voie hedgehog

Also Published As

Publication number Publication date
US20030109700A1 (en) 2003-06-12
US6878707B2 (en) 2005-04-12
ES2240420T3 (es) 2005-10-16
JP3897594B2 (ja) 2007-03-28
DE60110896T2 (de) 2006-01-12
AU2001237309A1 (en) 2001-07-31
ATE295836T1 (de) 2005-06-15
JP2003520270A (ja) 2003-07-02
EP1259484B1 (fr) 2005-05-18
DE60110896D1 (de) 2005-06-23
EP1259484A1 (fr) 2002-11-27
PT1259484E (pt) 2005-09-30

Similar Documents

Publication Publication Date Title
EP1259484B1 (fr) Carboxamides utilises comme inhibiteurs de proteine de transfert triglyceridique microsomique et de la secretion d'apolipoproteine b
US6197798B1 (en) Amino-benzocycloalkane derivatives
KR101839137B1 (ko) 히스톤 탈아세틸화효소 6 억제제로서의 옥사다이아졸 아민 유도체 화합물 및 이를 포함하는 약제학적 조성물
EP1536797B1 (fr) Derives de la 1-amido-4phenyl-4-benyloxymethyl-piperidine et composes similaires pour l'utilisation comme antagonists de la neurokinine-1 (nk-1) pour le traitement du vomissement, la depression, l'anxiete et le toux
US7098226B2 (en) TNF-α production inhibitors
KR20020005662A (ko) 질소함유 복소환화합물 및 벤즈아미드화합물 및 그 것을함유해서 되는 의약
NZ526893A (en) Isoindole-imide compounds, compositions, and uses thereof
WO1994018161A1 (fr) Sulfamides de phenyle substitues utilises comme agonistes a selectivite beta 3 dans le traitement du diabete et de l'obesite
JP2009541382A (ja) 新規なｃｘｃｒ２阻害剤
WO2012012322A1 (fr) Acides hydroxamiques substitués et leurs utilisations
WO2012012320A1 (fr) Acides hydroxamiques substitués et leurs utilisations
JP2007261945A (ja) チアゾール誘導体
JPWO2003061658A1 (ja) インダノン誘導体を含有するシグマ受容体結合剤
EP1734961A2 (fr) Procedes de traitement de l'amylose mettant en oeuvre des inhibiteurs de la protease a base d'aspartyle bicyclique
WO2000005201A1 (fr) Derives n-benzocycloalkyl-amide et leur utilisation comme medicaments
AU2019247842B2 (en) Opioid receptor modulators and products and methods related thereto
WO2002020462A1 (fr) Derives d'acide benzoique et medicaments possedant ces derniers comme principe actif
HU224354B1 (hu) 2-Aminoindán-származékok alkalmazása és az ezeket tartalmazó gyógyszerkészítmények
KR100620406B1 (ko) 콜린작용 활성을 강화시키기 위한 아미드 화합물
EP0983243B1 (fr) Nouveaux quinoline- et naphthalenecarboxamides, compositions pharmaceutiques et procedes d'inhibition de la calpaine
WO2001005767A1 (fr) Composes organiques
AU2005296674B2 (en) Ester derivative and pharmaceutical use thereof
US8980938B2 (en) CXCR2 inhibitors
CN100384824C (zh) 乙酰基2-羟基-1,3-二氨基烷烃
US8101774B2 (en) Ester derivatives and medicinal use thereof

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2001909632

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 10181006

Country of ref document: US

ENP Entry into the national phase

Ref country code: JP

Ref document number: 2001 553264

Kind code of ref document: A

Format of ref document f/p: F

WWP Wipo information: published in national office

Ref document number: 2001909632

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWG Wipo information: grant in national office

Ref document number: 2001909632

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载